Controlled-release compositions of melatonin combined with sedative and/or analgesic ingredients

ABSTRACT

Controlled-release therapeutic compositions including melatonin combined with sedative and/or analgesic ingredients are described. The compositions have a solid core including melatonin in an acidified polymeric matrix. A sedative ingredient such as GABA receptor agonist may also be in the acidified polymeric matrix. The composition may include an expedited release portion providing a burst release of active ingredients and a sustained release portion providing a sustained release of active ingredients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 15/371,868, which is adivisional of application Ser. No. 15/148,665, filed May 6, 2016, whichis a continuation-in-part of application Ser. No. 14/942,299, filed Nov.16, 2015, which is a division of application Ser. No. 14/186,599, filedFeb. 21, 2014, now U.S. Pat. No. 9,186,351, which is a continuation ofapplication Ser. No. 13/359,638, filed Jan. 27, 2012, now U.S. Pat. No.8,691,275, which claims priority to provisional application Ser. No.61/437,217, filed Jan. 28, 2011. Each of these prior applications isincorporated by reference in its entirety.

FIELD

This relates to the field of melatonin compositions and, moreparticularly, to controlled-release melatonin compositions.

SEQUENCE LISTING

The application contains a Sequence Listing electronically submitted viaEFS-web to the United States Patent and Trademark Office as a text filenamed “Sequence_Listing.txt.” The electronically filed Sequence Listingserves as both the paper copy required by 37 C.F.R. § 1.821(c) and thecomputer readable file required by 37 C.F.R. § 1.821(c). The informationcontained in the Sequence Listing is incorporated by reference herein inits entirety.

BACKGROUND

Melatonin is a hormone secreted by the pineal gland, a smallpinecone-shaped gland located near the center of the brain. Its chemicalformula is N-acetyl-5-methoxytryptamine, which is a derivative of theamino acid tryptophan and serotonin. The pineal gland secretes melatoninin a circadian rhythm, which is an approximately 24 hour cycle in thebiochemical, physical, or behavioral processes of an organism. Acircadian rhythm is an endogenous, or built-in function that is adjustedby environmental stimuli, such as daylight. It is known that the bodyplasma concentration of melatonin is low during the daytime, starts torise during the late evening, and is maintained at 25-120 pg/mL duringthe night (over 8 hours) until it returns to the daytime baseline.

Exogenous, or synthetic melatonin has been proposed to have therapeuticpotential in human subjects for treating melatonin deficiency, circadianrhythm disorders, sleep disorders, jet lag, shift work syndrome, andseasonal affective diseases. Some suggest that melatonin may also beeffective in the treatment of breast cancer, fibrocystic breastdiseases, and colon cancer. Melatonin has been shown to modify theimmune response, the stress response, certain aspects of the agingprocess, sleep disturbances in Alzheimer's patients, and oxidativestress. This suggests a plethora of beneficial uses for melatonin.

Exogenous melatonin treatments suffer from several problems. Melatoninis eliminated from the blood quickly once administered. It has a plasmaelimination half-life of less than one hour. When administered orally,it shows low and variable bioavailability. As with most oraladministrations, it can take more than 30 minutes after ingestion forthe blood plasma concentration of melatonin to reach its peak. This ispartly due to the need for release of the melatonin from the dosage formfollowed by permeation through the wall of the gastrointestinal tractfor absorption to occur before the melatonin can enter the bloodstream.

Melatonin is slightly soluble, has good permeability characteristics,and is in the class II category according to the BiopharmaceuticsClassification System. Therefore, the amount of melatonin available forabsorption into the bloodstream primarily depends on its solubility.Melatonin's solubility generally decreases in less acidic environments.Because the pH of the gastrointestinal tract varies significantly,different amounts of melatonin are available for absorption into thebloodstream, depending on the region of the G.I. tract the melatoninenters.

Orally administered immediate and controlled release melatoninformulations exist. Studies indicate large inter-subject variability ofmelatonin in the blood plasma of human subjects given melatonin orally.Other problems reported include poor oral bioavailability and anutritional status effect on the oral bioavailability.

Various formulations of melatonin have been developed to provide releaseof melatonin over a 3 to 10 hour period to stimulate the body's naturalrelease of melatonin. These formulations have not gained wide acceptancebecause of their variable response in patients. Patients may experiencemiddle of the night awakening, early morning grogginess, and sleep timesof less than 5 hours.

Other natural products besides melatonin are often marketed as dietarysupplements, but most dietary supplements are only available in a dosageform that releases all of the active ingredients quickly once the dosageform starts dissolving in the body.

BRIEF SUMMARY

In view of the foregoing, it would be advantageous to have acontrolled-release dosage form including melatonin in combination withone or more other active ingredients that work in concert withmelatonin, such as sedative and/or analgesic ingredients.

A first example of such a composition comprises a pharmaceutical dosageform having a solid core including a combination of melatonin and a GABAreceptor agonist ingredient located together within a first acidifiedpolymeric matrix THAT may have a pH of about 1 to about 4.4. Anexpedited release portion of the dosage form includes 5% to 50% of theGABA receptor agonist ingredient in the dosage form. The expeditedrelease portion is effective to release substantially all of the GABAreceptor agonist ingredient therein within about 2 hours from placementin a 0.1 N HCl solution. A sustained release portion of the dosage formincludes the remainder of the of GABA receptor agonist ingredient in thedosage form. The sustained release portion is effective to releasesubstantially all of the GABA receptor agonist ingredient therein withinabout 10 hours from placement in a phosphate buffer with a pH of 6.8.

The sustained release portion may include a plurality of individualgranules that have the remainder of the GABA receptor agonist ingredientin the pharmaceutical dosage form therein.

The composition may further comprise an analgesic ingredient in theexpedited release portion.

The composition may further comprise an analgesic ingredient in theexpedited release portion and the sustained release portion may includea plurality of individual granules that have the remainder of the GABAreceptor agonist ingredient in the pharmaceutical dosage form therein.

The GABA receptor agonist ingredient may include valerian and theexpedited release portion may further include an analgesic ingredient.

The GABA receptor agonist ingredient may include valerian and theexpedited release portion may further include an analgesic ingredienthaving salicin therein.

The pharmaceutical dosage form may be at least one of a compressedtablet, capsule, and multiparticulate-containing oral dosage form.

In the expedited release portion, the 5% to 50% of the GABA receptoragonist ingredient in the pharmaceutical dosage form may be locatedwithin a second acidified polymeric matrix having a pH of about 1 toabout 4.4.

A second example of such a composition comprises a pharmaceutical dosageform having a solid core including a combination of melatonin and ananalgesic ingredient, the melatonin being located within a firstacidified polymeric matrix may have a pH of about 1 to about 4.4. Anexpedited release portion of the dosage form includes 5% to 50% of theanalgesic ingredient and the melatonin in the dosage form. The expeditedrelease portion is effective to release substantially all of theanalgesic ingredient and melatonin therein within about 2 hours fromplacement in a 0.1 N HCl solution. A sustained release portion of thedosage form includes the remainder of the analgesic ingredient andmelatonin in the dosage form. The sustained release portion is effectiveto release substantially all of the analgesic ingredient and melatonintherein within about 10 hours from placement in a phosphate buffer witha pH of 6.8.

The sustained release portion may include a plurality of individualgranules that have the remainder of the melatonin in the pharmaceuticaldosage form therein.

The composition may further comprise a GABA receptor agonist ingredientin the acidified polymeric matrix.

The analgesic ingredient may include a salicin source. The salicinsource may be a white willow bark extract that is at least about 75%salicin.

The pharmaceutical dosage form may be at least one of a compressedtablet, capsule, and multiparticulate-containing oral dosage form.

In the expedited release portion, the 5% to 50% of the analgesicingredient in the dosage form may be located within a second acidifiedpolymeric matrix having a pH of about 1 to about 4.4.

A third example of such a composition comprises a pharmaceutical dosageform having a solid core including a salicin source and a combination ofmelatonin and valerian, the melatonin and valerian being locatedtogether within a first acidified polymeric matrix may have a pH ofabout 1 to about 4.4. An expedited release portion of the dosage formincludes 5% to 50% of the salicin source, valerian, and melatonin in thedosage form. The expedited release portion is effective to releasesubstantially all of the salicin source, valerian, and melatonin thereinwithin about 2 hours from placement in a 0.1 N HCl solution. A sustainedrelease portion of the dosage form includes the remainder of the of thesalicin source, valerian and melatonin in the dosage form. The sustainedrelease portion is effective to release substantially all of the salicinsource, valerian, and melatonin therein within about 10 hours fromplacement in a phosphate buffer with a pH of 6.8.

The salicin source may be a white willow bark extract that is at leastabout 75% salicin.

The pharmaceutical dosage form may be at least one of a compressedtablet, capsule, and multiparticulate-containing oral dosage form.

In the expedited release portion, the 5% to 50% of the valerian andmelatonin in the dosage form is located within a second acidifiedpolymeric matrix having a pH of about 1 to about 4.4.

The sustained release portion may include a plurality of individualgranules that have the remainder of the valerian and melatonin in thepharmaceutical dosage form therein.

Any of these example compositions may be employed in a method oftreating a patient in need thereof by administering an effective amountof the composition to the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow diagram illustrating an embodiment of a low sheargranulation process.

FIG. 2 is a graph of the dissolution profile of examples of melatonincompositions of the invention.

FIG. 3 is a flow diagram illustrating an example of a high sheargranulation process for the manufacture of extended-release melatonintablets.

FIG. 4 is a graph of the dissolution profile of an example of anextended-release melatonin tablet.

FIG. 5 is a graph of the particle size distribution of an example of ahigh shear granulated melatonin placebo blend.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

The melatonin composition may include at least one sedative ingredientin combination with melatonin. Such sedative ingredients may include askeletal muscle relaxer, and/or a GABA modulator such as a GABA receptoragonist. Examples of sedative ingredients include, but are not limitedto, valerian, L-theanine, lemon balm, skullcap, and a decapeptide havingthe amino acid sequence Tyr-Leu-Gly-Tyr-Leu-Glu-Gln-Leu-Leu-Arg (SEQ IDNO: 1 YLGYLEQLLR), which is marketed as LACTIUM® (Ingredia SocieteAnonymeFrance) and described in U.S. Pat. No. 5,846,939.

Melatonin has been reported to have a pKa of approximately 4.4 to 4.7.This gives melatonin different degrees of dissociation and differentsolubilities as it travels through the GI tract due to pH changes. Inthe gastric environment, at a pH range of approximately 1 to 3, itssolubility is relatively high. In the upper GI tract environment, at apH range of approximately 4.5 to 5.5, its solubility decreases. In thelower GI tract environment, at a pH range of approximately 5.5 to 7, itssolubility decreases even further. This variability in the GI tract pHis not a major factor for conventional immediate-release melatonindosage forms, as melatonin is readily dissolved in the low pH of thegastric environment. Unfortunately, this results in the melatonin beingabsorbed and eliminated too quickly to mimic the pattern of theendogenous melatonin found in healthy young subjects.

A first embodiment of the composition includes melatonin in a polymermatrix with the sedative ingredient. In this embodiment it may bedesirable to use sufficient acidifying agent to impart a pH of 4.4 orbelow to the polymer matrix. Examples of such pH ranges include 0.1 to4.4, 1 to 4.4, 2 to 4.4, 3 to 4.4, 4 to 4.4, 1 to 4, 2 to 4, or 3 to 4.In this pH range the solubility of melatonin is enhanced compared to aneutral pH.

This may be useful for obtaining a sustained release of melatoninthroughout the GI tract. Melatonin is much more soluble in the stomachthan the intestines because the pH of the stomach is low whereas the pHof the intestines is higher. The acidified polymer matrix forms acontrolled pH carrier for the melatonin within the GI tract. Melatoninremains solubilized in the matrix when it absorbs water in the GI tractand can gradually release from the matrix as the dosage form passesthrough the GI tract, regardless of the GI tract's local pH environment.

The dosage form provides a sustained release of melatonin and thesedative ingredient. Such a product is useful as a sleep aid with dualtherapeutic functionality. The sedative ingredient will help the patientrelax prior to falling asleep. The melatonin will help the patient fallasleep and stay asleep through the night.

The dosage form is adapted to release an effective amount of sedativeingredient and melatonin within the pH range found in the intestinescontinuously for at least 3 and up to 10 hours. In a particular example,the dosage form is adapted to release melatonin over a period of 3-10hours after ingestion regardless of the pH environment it passesthrough. This sustained release of sedative ingredient and melatoninwill help the subject remain asleep through the night.

A second embodiment of the composition includes at least one analgesicingredient in combination with the sedative ingredient and melatonin.The analgesic ingredient will further provide pain relief.

Examples of analgesic ingredients include, but are not limited tosalicin, acetylsalicylic acid, sodium salicylate, acetaminophen,ibuprofen, diclofenac, ketoprofen, bromelain, and naproxen.

In a particular example of the composition, the analgesic ingredient isa salicin source, such as willow bark (Salix spp.) or willow barkextract. Salicin is pain relieving anti-inflammatory compound similar instructure to acetylsalicylic, which is the active ingredient in Aspirin.Willow bark may also contain other flavonoids that are analgesicingredients. Willow bark has been used to treat headaches, muscle pain,and arthritis among many other conditions.

The salicin source may contain willow bark from one or more willowspecies. There are various types of willow bark that contain salicin,including bark from the white willow (Salix alba), black willow (Salixnigra), crack willow (Salix fragilis), purple willow (Salix purpurea),and weeping willow (Salix babylonica). The amount of salicin in thewillow bark varies amongst species and age of the tree. If white willowbark is the salicin source, it may be desirable to choose a white willowbark extract containing at least 75%, 85%, or 95% salicin.

In the composition, the polymeric matrix effectively insulates themelatonin and sedative ingredient from the pH environment of the GItract. Instead of dissolving directly into the GI tract, the melatoninand sedative ingredient dissolve within the polymeric matrix, forming aconcentration gradient across the matrix. Melatonin and the sedativeingredient will then be released into the GI tract from the periphery ofthe matrix in this manner.

The polymer matrix is formed from at least one pharmaceuticallyacceptable polymeric excipient. Examples of polymeric excipientsinclude, but are not limited to: cellulosic polymers such ascarboxymethylcelluloses, methylcelluloses, hydroxypropylcelluloses, andhydroxypropylmethylcelluloses; hyaluronates; alginates; polysaccharides,heteropolysaccharides, pectins; poloxamers; poloxamines; ethylene vinylacetates; polyethylene glycols; dextrans; polyvinylpyrrolidones;chitosans; polyvinylalcohols; propylene glycols; polyvinylacetates;phosphatidylcholines, lecithins; miglyols; polylactic acid;polyhydroxybutyric acid; mixtures thereof, copolymers thereof,derivatives thereof, and the like.

In a particular example, the at least one polymeric excipient is ahydrogel-forming polymer. A hydrogel-forming polymer is a polymercapable of swelling by absorbing water. When ingested by a patient, thehydrogel-forming polymer absorbs water and swells. The activeingredient(s) in the core disperse through the formed hydrogel andgradually exit the hydrogel into the patient's gastrointestinal tract.The hydrogel-forming polymer may act as a release-controlling polymer toprovide a sustained release of active ingredient(s) into the GI tractover a desired time period.

Hydroxypropyl methylcellulose (“HPMC” or “hypromellose”) is used incertain particular formulations of the dosage form because it forms ahydrogel and is available in many different versions that vary bymolecular weight. Thus the properties of the dosage form can be variedby selecting different a different molecular weight version of HPMC.

The acidic pH is imparted to the polymer matrix by blending anacidifying agent such as an acid and/or an acidic buffer with thepolymeric excipient. Examples of acidifying agents include, but are notlimited to, acidic molecules including organic and/or inorganic acidicmolecules. Organic acidic molecules include, but are in no way limitedto, low molecular weight carboxylic acids such as citric acid, succinicacid, and tartaric acid. Inorganic acidic molecules include phosphoricacid and hydrochloric acid, for example. Acidic buffers can be preparedwith organic or inorganic acidic molecules. Acidic buffers such as monosodium citrate or mono potassium phosphoric acid (monopotassiumphosphate) are examples, but acidic buffers are in no way limited tothese.

The pharmaceutical dosage form will typically be an oral dosage formsuch as a tablet, caplet, capsule, multiparticulate, or the like. Insuch cases, the dosage form has a solid core containing one or more ofthe active ingredients within the polymer matrix.

The amount of acidifying agent is sufficient to impart an acidic pH tothe polymer matrix when it absorbs water and swells. Some suitableapproximate pH ranges for the polymer matrix include 0.1 to 7, 0.1 to 6,0.1 to 5, 1 to 6, 1 to 5, 2 to 6, 2 to 5, 2.5 to 5.5, 2 to 4.5, 3 to 6,3 to 5, 3 to 4.5, 3.3 to 5, or 3.4 to 4.5.

In the products discussed above the dosage form includes a sustainedrelease portion, which is the polymer matrix containing the activeingredient(s). The sustained release portion is effective to release theactive ingredient(s) therefrom into the patient's lower GI tract overabout 3 hours to about 10 hours after oral ingestion by the patient. Incertain cases, the dosage form will release substantially all of theactive ingredient(s) therefrom within 10 hours after oral ingestion orwithin about 8 hours after oral ingestion.

The dosage form may also include an expedited release portion. Theexpedited release portion is effective to release about 50% of theactive ingredient(s) into the lower GI tract within about 2 hours afteroral ingestion or about 1 hour after oral ingestion.

The expedited release portion of the dosage form can be formulated manydifferent ways. A few examples are described below, but these examplesare not an exhaustive list of the many possibilities.

The polymer matrix may function as both the expedited release portionand sustained release portion. This is because when the dosage formreaches the patient's stomach, it will begin releasing some of theactive ingredients from the polymer matrix almost immediately as thepolymer matrix absorbs water in the stomach. As the polymer matrixswells, a pH gradient forms within the matrix and the release rate ofthe active ingredients slows.

Another example of a dosage form with an expedited release portion andsustained release portion is a bi-layer tablet having one layer formingthe sustained release portion and another layer forming the expeditedrelease portion.

Another example of a dosage form with an expedited release portion andsustained release portion is a capsule containing the sustained releaseportion and expedited release portion. In such an example, the expeditedrelease portion may include particulates effective to release the activeingredients therein over a desired expedited time period and thesustained release portion may be another set of particulates effectiveto release the active ingredients therein for a sustained time period.

Another example of a dosage form with an expedited release portion andsustained release portion is a tablet or capsule in which the polymermatrix forms a solid core and the expedited release portion is in acoating over the core.

The relative dosage percentage of the expedited and sustained releaseportions can vary. In some examples, the expedited release portioncontains 5% to 50% or up to 65% of a particular active ingredient in thedosage form. In other examples, the sustained release portion containsup to 90% of a particular active ingredient in the dosage form. Inanother example, the expedited release portion contains approximately50% of the active ingredient(s). The active ingredients from theexpedited release portion are released approximately in the first twohours after ingestion. The active ingredients in the sustained releaseportion include the remainder of the active ingredient(s), which arereleased approximately over the next 5-8 hours or within about 10 hoursafter ingestion.

The release profile may be measured by simulating the GI tractenvironment by placing the dosage form in a 0.1 N HCl (hydrochloricacid) solution for two hours, then placing it in a phosphate buffersolution of pH=6.8 for 12 hours.

The release rate of the active ingredient(s) from the dosage form can becontrolled in several ways. The concentration of the activeingredient(s) may be adjusted. The pH of polymer matrix may be adjusted.One or more release rate controlling coatings may be included. Thethickness of such a coating may be adjusted. The size and shape of thedosage form may also be adjusted to provide the preferred release rate.

An effective amount is an amount that is sufficient to provide atherapeutic benefit affecting a disease or condition in the body.

A therapeutically effective amount of sedative ingredient, melatonin,and/or analgesic ingredient may be 1-1,000 mg/day, including 1-mg/day,25-50 mg/day, 50-75 mg/day, 75-100 mg/day, 100-150 mg/day, 150-200mg/day, 200-250 mg/day, 250-300 mg/day, 300-350 mg/day, 350-400 mg/day,400-450 mg/day, 450-500 mg/day, 500-550 mg/day, 550-600 mg/day, 600-650mg/day, 650-700 mg/day, 700-750 mg/day, 750-800 mg/day, 800-850 mg/day,850-900 mg/day, 900-950 mg/day, 950-1,000 mg/day. Higher doses(1,000-3,000 mg/day) might also be effective. The weight in mg is oftencalibrated to the body weight of the patient in kg, thus these exampledoses may also be written in terms of mg/kg of body weight per day.

If the dosage form includes L-theanine, an effective amount ofL-theanine may be 25-250 mg, 50-200 mg, or about 100 mg may be used.

If the dosage form includes skullcap, an effective amount of skullcapmay be 25-250 mg, 50-200 mg, or about 100 mg may be used.

If the dosage form includes lemon balm, an effective amount of lemonbalm may be 25-250 mg, 50-200 mg, or about 100 mg may be used.

If the dosage form includes the decapeptide, an effective amount of thedecapeptide may be 25-250 mg, 50-200 mg, or about 100 mg may be used.

In practice, the therapeutically effective amount may vary depending onnumerous factors associated with the patient, including age, weight,height, severity of the condition, administration technique, and otherfactors. The therapeutically effective amount administered to a patientmay be determined by medical personnel taking into account the relevantcircumstances.

The therapeutically effective amount may be determined or predicted fromempirical evidence. Specific dosages may vary according to numerousfactors and may be initially determined on the basis of experimentation.

The product may be administered as a single dose or as part of a dosageregimen. For a dosage regimen, the therapeutically effective amount isadjustable dose to dose to provide a desired therapeutic response.

Multiple doses may be administered at a predetermined time interval andsubsequent doses may be proportionally reduced or increased, dependingon the situation.

Table 1 is a list of a few of the possible therapeutically effectiveamounts of active ingredients in several examples of the composition,Examples A-H. Here, the mass is reported by weight of a unitary dosageform. This list is not meant to be exhaustive.

TABLE 1 Amounts of active ingredient(s) in examples of the composition.Mass (milligrams) Active A B C D E F G H sedative 100-400 150-300100-400 150-300 100-400 150-300 150-250 190-210 Melatonin 0 0  1-10 3-6 1-10 3-7 4-6 4-6 analgesic 0 0 0 0 150-550 200-300 240-270 250-275

Several particular examples of the composition will now be described.The scope of possible embodiments, however, is not limited to theseexamples. These examples are presented as percent by weight (% w/w) ofthe specified ingredient relative to the dosage form. If a coating isplaced over the dosage form, the % w/w is the pre-coating % w/w. Anycombination of the ingredients in the % w/w listed below may beemployed.

Melatonin may be 0.1%-5% w/w; 0.1%-2% w/w, 0.1% to 1% w/w, or 0.2%-0.7%w/w.

The sedative ingredient may be 10%-50% w/w, 15%-45% w/w, 15%-40% w/w,15%-35% w/w, 15%-25% w/w, 18%-24% w/w, or 20%-22% w/w.

The polymer excipient may be 0.5%-20% w/w, 1%-20% w/w, 1%-15% w/w, 1%-7%w/w, 1%-5% w/w, 2%-6% w/w, or 2%-4% w/w.

The acidifying agent may be 0.5%-20% w/w, 1%-20% w/w, 1%-15% w/w, 5%-15%w/w, 2%-10% w/w, 7%-15% w/w, 6%-10% w/w, or 7%-9% w/w.

The binder may be 0.5%-20% w/w, 2%-15% w/w, 9%-33% w/w, 10%-20% w/w,12%-20% w/w, 12%-18% w/w, or 15%-17% w/w.

The analgesic ingredient may be 15%-60% w/w, 15%-50% w/w, 20%-60% w/w,20%-55% w/w, 25%-35% w/w, or 26%-30% w/w.

A more particular example of the composition includes: about 15% toabout 45% w/w of sedative ingredient; about 0.1% to about 2% w/wmelatonin; about 1% to about 15% w/w of acidifying agent; about 1% toabout 15% w/w of hydrogel-forming polymer; and about 10% to about 20%binder.

Another more particular example of the composition includes: about 15%to about 45% w/w of sedative ingredient; about 0.1% to about 2% w/wmelatonin; about 20% w/w to about 55% w/w salicin source; about 1% toabout 15% w/w of acidifying agent; about 1% to about 15% w/w ofhydrogel-forming polymer; and about 10% to about 20% binder.

The expedited and sustained release portions may be formulatedseparately then combined into the final dosage form. For example, thesustained release portion can be formed from a plurality of individualgranular particulates that contain the acidified polymeric matrix andactive ingredients. Likewise the expedited release portion can be formedfrom a plurality of individual granular particulates that contain itsactive ingredients. If melatonin and/or a GABA receptor agonist isincluded in the expedited release portion, the expedited release portionmay also include an acidified polymeric matrix.

In another example, the composition includes a pharmaceutical dosageform that has a solid core including a combination of melatonin and aGABA receptor agonist ingredient located together within a firstacidified polymeric matrix having a pH of 1 to 4.4. An expedited releaseportion of the dosage form includes 5% to 50% of the GABA receptoragonist ingredient in the dosage form. The expedited release portion iseffective to release substantially all of the GABA receptor agonistingredient therein within about 2 hours from placement in a 0.1 N HClsolution. A sustained release portion of the dosage form includes theremainder of the of GABA receptor agonist ingredient in thepharmaceutical dosage form. The sustained release portion is effectiveto release substantially all of the GABA receptor agonist ingredienttherein within about 10 hours from placement in a phosphate buffer witha pH of 6.8.

In another example, the composition includes a pharmaceutical dosageform that has a solid core including a combination of melatonin and ananalgesic ingredient. The melatonin is located within a first acidifiedpolymeric matrix having pH of 1 to 4.4 An expedited release portion ofthe dosage form includes 5% to 50% of the analgesic ingredient and themelatonin in the dosage form. The expedited release portion is effectiveto release substantially all of the analgesic ingredient and melatonintherein within about 2 hours from placement in a 0.1 N HCl solution. Asustained release portion of the dosage form includes the remainder ofthe analgesic ingredient and melatonin in the dosage form. The sustainedrelease portion is effective to release substantially all of theanalgesic ingredient and melatonin therein within about 10 hours fromplacement in a phosphate buffer with a pH of 6.8.

In another example the composition includes a pharmaceutical dosage formhaving a solid core that includes a salicin source and a combination ofmelatonin and valerian. The melatonin and valerian are located togetherwithin a first acidified polymeric matrix having a pH of 1 to 4.4. Anexpedited release portion of the dosage form includes 5% to 50% of thesalicin source, valerian, and melatonin in the dosage form. Theexpedited release portion is effective to release substantially all ofthe salicin source, valerian, and melatonin therein within about 2 hoursfrom placement in a 0.1 N HCl solution. A sustained release portion ofthe dosage form includes the remainder of the of the salicin source,valerian and melatonin in the dosage form. The sustained release portionis effective to release substantially all of the salicin source,valerian, and melatonin therein within about 10 hours from placement ina phosphate buffer with a pH of 6.8.

As mentioned above, the dosage form will typically be an oral dosageform such as a tablet, caplet, capsule, multiparticulate, or the like.One or more pharmaceutically acceptable excipients aside from thosedescribed already may be used to obtain the desired dosage form and giveit the desired properties.

Examples of excipients include, but are not limited to, carriers,diluents, disintegrants, emulsifiers, solvents, processing aids,buffering agents, colorants, flavorings, solvents, coating agents,binders, carriers, glidants, lubricants, granulating agents, gellingagents, polishing agents, suspending agent, sweetening agent,anti-adherents, preservatives, emulsifiers, antioxidants, plasticizers,surfactants, viscosity agents, enteric agents, wetting agents,thickening agents, stabilizing agents, solubilizing agents,bioadhesives, film forming agents, emollients, dissolution enhancers,dispersing agents, or combinations thereof.

Tablets and caplets may be prepared using conventional tabletingtechniques such as dry blending or wet granulation. The dry blend orgranulation may be compressed into a final tablet form.

Capsules may be prepared using different techniques. For example, driedgranules produced by wet granulating the ingredients may be loaded intoa capsule, such as a gelatin capsule.

A spray granulation process may be used to prepare the dosage form aswell. The spray granulation process produces granular cores containingthe active ingredients, the polymer matrix, and the acidifying agent.The granular cores may be combined into a final dosage form such as bycompressing them into a tablet or loading them into a capsule, forexample.

Alternatively, the capsules may be loaded with individual spheroidalmultiparticulates having a diameter of from about 0.5 mm to about 4 mmor from about 0.5 mm to about 3 mm that are prepared by forming a wetmass of the ingredients, extruding the wet mass, cutting the extrudedwet mass into pieces, and spheronizing the pieces. The individualparticulates may include any of the coatings discussed here.

When preparing the dosage form, it may be desirable to include asolubilizing agent to help solubilize the melatonin. Solubilizing agentsinclude, but are not limited to, polyethylene glycol (PEG) basedsurfactants. The molecular weight of PEG can be chosen to provide thedesired properties of the composition. A solubilizing agent may not beneeded in every embodiment of the dosage form.

Conventional processing aids may be used to prepare dosage form.Examples of processing aids include, but are not limited to, magnesiumstearate, stearic acid, talc, and sodium lauryl sulfate.

The dosage form may include a pharmaceutically acceptable filler.Examples of fillers include, but are not limited to, silicates, calciumcarbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate,calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, drystarches and powdered sugar.

The dosage form may include a pharmaceutically acceptable binder.Examples of binders include, but are not limited to, cellulosic, andpovidone binders such as microcrystalline cellulose and crospovidone.

Examples of dispersing agents include, but are not limited to, copolymersystems such as polyethylene glycol-polylactic acid (PEG-PLA),polyethylene glycol-polyhydroxybutyric acid (PEG-PHB),polyvinylpyrrolidone-polyvinylalcohol (PVP-PVA), and derivatizedcopolymers such as copolymers of N-vinyl purine or pyrimidinederivatives and N-vinylpyrrolidone.

The dosage form may be coated to aid in swallowing, to mask the taste ofthe ingredients, improve appearance, to protect the dosage form frommoisture, and/or to have an enteric coating. The coating may be appliedusing conventional coating techniques, such as, for example, spraycoating, bed coating, or the like.

The dosage form may be coated with an enteric coating to substantiallyprevent the active ingredients from releasing into the stomach. Examplesof enteric coating materials include shellac, cellulose acetatephthalate, polyvinyl acetate phthalate, ethyl cellulose/sodium alginate,hypromellose acetate succinate, or a methacrylic acid-based polymer orco-polymer such as methacrylic acid—ethyl acrylate copolymer.

The dosage form may be coated with a seal coating. Examples of sealcoating materials include, but are not limited to, hydroxypropylcellulose, hypromellose, and polyvinyl alcohol. A particular example ofthe seal coating is OPADRY® Clear (Colorcon, Inc.), which contains, HPMCand polyethylene glycol.

More particular examples of the composition in which valerian is thesedative ingredient are now described. The term “valerian” as usedherein includes valerian root, valerian extracts, and thetherapeutically active compounds in valerian such as valerenic acidand/or valepotriates such as valtrate and didrovaltrate. Valerian may bein a dried root, powder, or liquid form. The liquid form contains theactive components of the valerian root suspended in a solvent. Alcoholsare typically used as the extraction solvent, but the liquid form mayalso be an oil.

In conventional aqueous or hydroalcoholic extracts or tinctures ofvalerian, the primary water-soluble active compound has been reported tobe isovaleric acid. Ammonium isovalerate and isovaleramide are producedin ammoniated tinctures. Valepotriates and monoterpene isovalerateesters, such as bornyl and lavandulyl isovalerates, are reported to actas prodrugs for isovaleric acid, its salts, and isovaleramide.

An embodiment of the valerian-containing composition includes avalerian-containing pharmaceutical dosage form in which valerian is inthe polymer matrix with an acidic pH. The acidic pH helps stabilize someof the bio-active compounds in valerian to enhance the storage stabilityof the valerian-containing composition.

The pKa of valerenic acid and valproic acid is reported to be about 5.In some examples of the composition, it is desirable to use sufficientacidifying agent to impart a pH of 5 or below in order to maintainvalerenic acid and valproic acid their protonated forms. It is believedthat imparting such a pH to the polymer matrix will help preventoxidative degradation to these acids.

Although not intended to be bound by theory, it is believed that one ofthe valerian degradation pathways is decarboxylation of the carboxylicacids such as valerenic acid. Using a carboxylic acid-based acidifyingagent may help mitigate decarboxylation. Because decarboxylation maybecome favorable at elevated temperatures, it is believed that acarboxylic acid-based acidifying agent may improve the storage stabilityof valerian.

Valerian has been reported to have both a foul smell and taste. Ifdesired, the dosage form may include a taste and/or smell-maskingcoating.

Valerian also contains volatile components, which may evaporate andleave the dosage form during storage. An evaporation-preventativecoating may be applied over the core to minimize evaporation of thesecomponents. An example of such an evaporation-preventative coating is agelatin coating. In some cases, acid bone gelatin may be a desirablesource of gelatin.

The polymeric matrix may function to prevent oxidative degradation ofvalerian. It provides a moisture and oxygen barrier during storage,which substantially prevents moisture and oxygen from penetrating intothe dosage form.

The composition in any of the forms described above may be used to treatone or more conditions such as pain, insomnia, anxiety, melatonindeficiency, a sleep disorder, and/or a circadian rhythm disorder.

A patient in need of treatment may be treated by administering thecomposition described above to the patient. The product may beadministered orally. The patient may be a human or animal patient.

EXAMPLES

This section describes a few specific examples of the composition. Theseexamples are presented by way of example only and are not intended tolimit the scope of the invention.

Example 1 Tablet Melatonin Composition

A. Experimental Details. Melatonin (Nutri-Force, lot number 81120) wasused in the following experiments. The melatonin was reported to be amicronized grade. Shipment, handling and processing of melatonin andprototypes were all under ambient room temperature. In-process materialsand bulk tablets were stored in double polyethylene bags with desiccant.Melatonin was evaluated for appearance and particle size by sieveanalysis.

Melatonin was visually characterized as a white to off-white poorflowing, fine powder. The particle size sieve analysis of melatoninrevealed a non-Guassian distribution of particles predominately of 150microns. Manufacture of the melatonin controlled-release tabletsdissolves the melatonin in a solution of polyethylene glycol and wateras part of the granulation fluid. Therefore, the particle size of themelatonin has no substantial effect on the final properties of thetablet, but did influence the rate at which the melatonin was dissolvedduring manufacture.

The following equipment was used preparing the formulations: KitchenAide planetary mixer; hot plate/magnetic stirrer; #6, 20 and 40 meshsieves; tray drying oven; comil with 0.039″ round hole screen; PiccolaB/D 8 station R&D press 0.455″×0.190″ capsule shaped tooling; ComputracLOD instrument; tablet hardness tester; tablet friability tester; andcalipers.

B. Development of 2 mg melatonin controlled-release tablets. Thissection describes the development of prototype tablets in accordancewith the invention. A hypromellose based monolithic tablet was utilizedto achieve the targeted 6-8 hours extended release of the 2 mgmelatonin. The formulation was varied as presented in Table 1 toidentify a formulation with the targeted release profile. The tabletsize was held constant throughout the experimentation at 250 mg with astrength of 2 mg melatonin per tablet. The formulations were prepared insmall 200-300 g batches.

It was discovered that hypromellose exhibited undesirable flowcharacteristics. For this reason, a granulation process was used. Theprototypes were manufactured using a low shear wet granulation processin a planetary mixer. The intra-granular components were charged to themixing bowl and granulated either with water in the early prototypes ora solution of water, polyethylene glycol and melatonin in the laterprototypes. The wet granulation was wet milled through a 6 mesh handsieve to break up any large agglomerates and then oven tray dried at 60°C. to a ˜1-3% moisture level. The dried granulations were milled to sizewith a Comil cone type mill using a 0.55″ screen initially and later a0.039″ screen. The extra-granular excipients were bag blended into themilled granulation and the final blend was compressed on a Piccolatablet press using 0.455″×0.190″ capsule shaped tooling to a tabletweight of 250 mg and hardness of ˜5 kp. The process used for the leadprototype lot CYV45-002-048A is summarized in the flow diagram of FIG.1.

Analysis of Prototypes. A two stage dissolution procedure in a USPdissolution apparatus type III with 2 hour in 0.1 N hydrochloric acidfollowed by 12 hours in pH 6.8 phosphate buffer was used to evaluate theprototypes. This was later simplified to a single stage procedure in0.9% saline when the two methods were shown to give equivalent results.Melatonin assay and related substance testing was performed by HPLC onthe identified lead prototype, which was CYV45-002-48A.

Four different matrix forming hypromellose grades of varying molecularweight (K4M, K15M, K100LV and E50) were initially screened (LotsCYV45-002-004, 007, 011 and 012) as presented in Table 1. Thehypromellose E50 hypromellose proved to be the most promising of thepolymers evaluated, but it still released the melatonin slower thandesired. The dissolution results are presented in FIG. 2.

Citric acid was first included in the formulation at a concentration of16% but was increased to approximately 30% to maintain a low pH in thetablet matrix, enhancing the aqueous solubility of the melatonin.STARCAP® 1500 (BPSI Holdings, LLC) starch was initially added at aconcentration 28% but was reduced to 12% to make room for the addedcitric acid without increasing tablet size.

The aqueous solubility of the melatonin was further increased, bydissolving the melatonin in a 50% solution of polyethylene glycolsurfactant (PEG 3350) and spraying the solution into the granulation.The use of the PEG 3350 successfully increased the dissolution rate.

Concurrently, the effect of granulation particle size on the dissolutionwas evaluated by using a Quadro Comil with either a 0.055″ or 0.039″round hole screen (lot CYV45-002-021A and B). The particle size of thegranulation had little effect on dissolution rate but the smallerparticle size granules was observed to generate less inter-tabletvariability in the dissolution data. As a result, the use of the 0.039″screen was adopted for use in subsequent trials.

It was discovered that compression of the tablets with the PEG 3350 wasnot ideal. Sticking in the cups of the tablet punches was noted causingcosmetic defects, erratic tablet weight and hardness. To alleviate thesticking problem, higher molecular weight PEG 8000 was substituted forthe use of the PEG 3350 in the formulation (lot CYV45-002-030).

The batch was also scaled up to a 1 kg size and processed using a highshear granulator and fluid bed in place of the low shear planetary mixerand tray drying oven used previously. This was done to provide amplematerial to compress for an extended period to investigate the tabletsticking issue and adapt the process to be more suitable for futuremanufacturing. The scaled up process is summarized in the flow chart ofFIG. 3. The equipment used in the scaled up process included thefollowing: Fielder PP1 High Shear granulator; Niro-Aeromatic MP-1Multi-processor; Fitzmill J mill equipped with a 0.040 round holescreen; 2 Qt PK Blender; Piccola Eight Station B/D tablet press;0.1920″×0.4570″ capsule shape tooling embossed with “REM” embossed inupper punch; Accela-cota model 24MK III (24″ coating pan; hot plate;Overhead mechanical lab stirrer and propeller; and 20 mesh, 6 mesh and40 mesh sieves.

The tablets were also film coated with an OPADRY® II Blue non-functionalcoating to simulate the eventual final product that was desired. Thegranulation, blend and tablets processed well at the increased scaleusing the high shear granulation process. The sticking problem duringtablet compression was alleviated. Coating was conducted successfullywith no difficulties. It was discovered that melatonin dissolution wasundesirably retarded by the substitution of PEG 8000 for PEG 3350.Accordingly, the formulation was tweaked to optimize the melatonindissolution.

To compensate for the slower release of melatonin, a small trialformulation with PEG 8000 (lot CYV45-002-048B) was made shifting aportion of the intra-granular citric acid to extra-granular to increasedissolution by increasing the porosity of the tablet matrix. Also, asmall trial batch (lot CYV45-002-048A) utilizing the PEG 8000 butreducing the concentration of the matrix forming polymer hypromelloseE50 from 30% to 20% was made and evaluated. The tablet weight was heldconstant by adding additional extra-granular ProSolv which alsoincreased the hydrophilicity of the tablet to accelerate the release ofthe melatonin. Both approaches increased dissolution rate. LotCYV45-002-048A with reduced level of E50 (20%) best fit the targetdissolution profile (FIG. 4). Table 2 lists the ingredients in thisformulation.

The physical properties of the final blend and compressed tablets forthe CYV45-002-048A prototype are presented in Tables 3 and 4 and FIG. 5.The particle size of the final blend is non-Guassian and somewhatbi-modal. The flow of the final blend was acceptable as indicated by ablend compressibility of 14% and Flodex critical orifice value of 16 mm.The formulation is preferably compressed with tablet presses utilizing apaddle feeder to ensure good flow and ensure that particle sizesegregation does not occur in the press feed frame.

The compressed tablets had low tablet weight variation. Tablet hardnessand thickness also exhibited low variability. The mean tablet hardnesswas 3.9 kp with a range of 3.4-4.2 kp. At first glance, this wouldappear to be low tablet hardness; however, this provided a robust tabletwith extremely low friability (0.03% lost in 100 drops) suitable forcoating in a tablet coating pan. Because the tablets comprised both PEGand citric acid, the tablets were soft due to plastic deformation;however, this softness is advantageous as it imparts a high degree ofimpact resistance. The capsule-type shape of the tablets itself with alow cross-sectional area generates deceptively low tablet hardnessvalues.

Prototype Lot CYV45-002-048A was assayed for melatonin and relatedsubstances and the results are presented in Table 5. The high assayvalue of 105.2% can largely be explained as a result of loss of moistureduring the granulation drying process. The excipients and melatoninprior to granulation contained 5.1% moisture as determined in a baselineloss on drying evaluation but only contained 1.2% after the granulationwas dried; thereby, making the granulation 3.9% super-potent. Thegranulation moisture will preferably be dried to level approximate tothe baseline moisture in future batches.

Because maintaining a low pH in the tablet matrix over the course of therelease was a desired property, tablets of CYV45-002-048A were placed indissolution baths containing saline for up to 7 hours at 50 rpm paddlespeed. The “ghost” cores remaining after 7 hours were decanted away andpH of the tablet cores was determined. At 4 hrs the pH was determined tobe 2.5 and at 7 hrs it was 2.8. This indicates that citric acid remainedin the tablet for an extended period of time to lower the pH and assistin the solubilization of the melatonin.

Preparation of Final Tablet. The formulation development activitiessuccessfully identified a controlled-release prototype for 2 mg dosestrength melatonin tablet. The in-vitro dissolution release profile metthe desired objective of releasing half the melatonin with 1-2 hoursfollowed by first order release with greater than 90% release achievedat 6 hours. The release of melatonin was shown to be independent of thepH of the dissolution media with similar profiles generated using anacid/pH 6.8 two stage dissolution versus a single stage saline method.The in-vitro dissolution data suggests the tablets will releasemelatonin quickly to induce sleep and maintain a level of melatonin forup to 6 hours with little melatonin remaining to create grogginess uponawakening. The formulation utilizes GRAS excipients and can bemanufactured by a high shear wet granulation process suitable formanufacture in a production facility.

Using the experimental results described above, a final tabletcomprising melatonin was prepared. The final tablet comprises theingredients shown in Table 6 and was prepared according to the procedurethat will now be described.

A granulation solution was first prepared by:

(a) charging 58.0 g of purified water to a beaker and heating toapproximately 60° C.;

(b) stirring and dissolving 50.0 g of PEG 8000 in the solution of (a);

(c) dissolving 8.0 g of melatonin in the solution of (b), resulting in aclear amber solution; and

(d) allowing the solution of (c) to cool to room temperature.

High shear wet granulation and wet milling was next performed by:

(a) screening the microcrystalline cellulose, citric acid andhypromellose through a 20 mesh sieve and charge to a Niro PP-1 highshear granulator;

(b) mixing the materials in the granulator for approximately threeminutes at a speed of 300 rpm;

(c) continued mixing and sprayed the granulation solution on the mixingmaterials over the course of about 3 minutes;

(d) while continuing mixing, spraying and additional 157 g of water overthe course of approximately 5 minutes;

(e) wet massing the granulation by mixing and additional 2-3 minutes;and

(f) discharging the product of (e) from the granulator and sizing thegranulation through a 0.156″ square hole screen using a Quadro Comil.

Drying granulation and dry milling was next performed by:

(a) charging the wet milled granulation to a Niro MP-1 fluid bed dryerand drying at an air inlet temperature of 60° C.;

(b) drying the product of (a) to approximately 2% moisture content (asdetermined by an LOD loss on drying instrument—the drying time wasapproximately 25 minutes);

(c) passing the product of (b) through a Fitzmill J mill at a slow speedin the knives forward mode using a 0.040″ round hole screen.

Final blending was achieved by:

(a) charging the dried milled granulation to a 2 quart V-blender;

(b) screening the Cabosil colloidal silicon dioxide through a 20 meshsieve and charging to the blender;

(c) blending the product of (b) for 120 revolutions;

(d) screening the magnesium stearate through a 40 mesh sieve andcharging to the blender; and

(e) blending the product of (d) for 72 revolutions.

The final blend was compressed into a tablet by:

(a) equipping a Piccola BD 8 station rotary tablet press with0.1920″×0.0.4570″ capsule shaped tablet tooling;

(b) loading the tablet press with the final blend; and

(c) compressing tablets to the following targets: tablet weight=250 mg,tablet hardness=8 kp, tablet thickness=0.185″.

TABLE 1 Formulations of 2 mg Melatonin Extended Release TabletDevelopment Prototypes % w/w Lot # CYV45-002- Ingredient 004 007 011 01221A/B 030 48A 48B Intra- Melatonin 0.8 granular (2 mg/tablet) Comp-Hypromellose 30 onents K4M Hypromellose 30 15M Hypromellose 30 K100LVHypromellose 30 30 30 20 30 E50 PEG 3350 5 PEG 8000 5 5 5 Citric Acid 1616 32 32 27 27 27 17 Starch 28 28 12 12 12 12 12 12 MCC 12.2 Extra-PROSOLV ® 12 12 12 12 12 12 22 12 granular HD90 Comp- Citric acid 10onents CAB-O-SIL ® 0.5 Mag Stearate 0.5 Total 100%

TABLE 2 Quantitative Formula for Melatonin 2 mg ER Tablets LeadPrototype Lot # 11216-048A Materials 2 mg Vendor/Lot # FunctionalityTablet % w/w g/Batch Gran. Soln Melatonin melatonin 2.0 0.8   2.4(Nutri-Force lot # 81120) Purified Water¹ Granulation NA NA 15 g for PEGsolvent solution + 33.5 g for granulation Polyethylene GlycolSolubilizer 12.5 5.0 15 PEG8000 (Dow) Intragranular MicrocrystallineCellulose, Diluent 30.5 12.2   36.6 NF AVICEL ® PH-101 (FMC) Citric AcidMonohydrate Acidifier 67.5 27.0 81 Powder (Spectrum) AcidifierCo-processed Starch Diluent/ 30 12.0 36 STARCAP ® 1500 binder (Colorcon)Hypromellose METHOCEL ® Matrix Polymer 50.0 20.0 60 E50 (Dow)Extragranular² PROSOLV ® HD90 JRS Diluent 55.0 22.0 66 Pharma)CAB-O-SIL ® M-5P (Cabot) Glidant 1.25 0.5    1.5^(b) Magnesium Stearate(Veg. Lubricant 1.25 0.5    1.5^(b) Source, Product Code 2257), NF/EP/JPTotal 250.0 100.0% 300 g ¹Removed upon drying ²Adjusted based ongranulation yield

TABLE 3 Melatonin 2 mg Extended Release Prototype Final Blend PhysicalProperties Bulk Density 0.43 g/mL Tap Density 0.50 g/mL Compressibility14.4% Flodex Flow 16 mm critical orifice Sieve Analysis % Retained 600μm 19.8 425 μm 15.1 300 μm 10.0 180 μm 16.5 106 μm 20.6  45 μm 17.1 <45μm  0.1

TABLE 4 Properties of Melatonin 2 mg Extended Release Tablet- PrototypeLot CYV45-002-048A Property Results Tablet Press Eight station PicollaB/D press (one station used) Tablet Tooling FDL-041: 0.455″ × 0.190″capsule shaped, plain faced Tablet Press Speed 40 rpm Main compressionForce 4.2 kiloNewtons Precompression Not used Ejection Force 92 NewtonsMean Tablet weight* 251 mg (range 249-253 mg % RSD = 0.5) Mean TabletHardness* 3.9 (range 3.4-4.2, % RSD = 6.2) Mean Tablet Thickness* 0.196″(range 0.195-0.196″, % RSD = 0.2) Tablet Friability 0.03% for 100 drops*10 tablets chosen at random from compression of 300 g batch

TABLE 5 Melatonin Assay/Related Substances of 2 mg Melatonin ExtendedRelease Tablets Lot CYV45-002-048A Melatonin Assay 105.2% ReportableImpurities (>0.10%) 0.18% @RRT 1.47 Total Impurities  1.8%

TABLE 6 Composition of Final Tablet Materials Vendor/Lot # 2 mg Tablet %w/w g/Batch Purified Water NA^(a) NA^(a) 58 g for PEG solution + 157 gfor granulation^(a) Melatonin 2.0 0.8 8.0 PEG8000 12.5 5.0 50.0Microcrystalline 144.25 57.7 577.0 Cellulose, NF AVICEL ® PH102 CitricAcid Powder 12.5 5.0 50.0 Hypromellose 75.0 30.0 300 METHOCEL ® E50CAB-O-SIL ® Colloidal 1.25 0.5 5.0 Silicon Dioxide Magnesium Stearate2.50 1.0 10.0 Total Prior to Coating 250.0 100.0% 1000 g ^(a)Water wasused as a solvent and granulation fluid and was removed duringprocessing.

Example 2 Melatonin and Valerian Composition

In this prospective example, the composition includes valerian incombination with melatonin. The composition is prepared as a two-partdosage form. The dosage form includes an expedited release portion and asustained release portion. The contents of the valerian product aresummarized in Table 7. SR indicates that the ingredient is part of thesustained release portion. ER indicates that the ingredient is part ofthe expedited release portion.

TABLE 7 Contents of dosage form % w/w % w/w of Mass of dosage PortionIngredient (mg) portion form SR Valerian root extract 200 39.1 21intragranular SR melatonin 5 0.1 5 intragranular SR Hypromellose 28 5.53 intragranular (PHARMACOAT ® 615) SR Citric acid 75 14.7 8intragranular SR MCC 150 29.4 16 extragranular SR Hypromellose 50 9.85.4 extragranular (METHOCEL ® K4M) SR Silicon dioxide 2.5 0.49 0.27extragranular 510.5 ER WWB extract 263 62.5 28 extragranular ERSilicified MCC 150 35.7 16 extragranular ER Mg stearate 7.5 1.8 0.8extragranular 420.5 TOTAL WEIGHT 931

The sustained release portion is prepared via a spray granulationprocess, such as top spray or tangential spray fluidized bed granulationprocess. In this process, granules containing the valerian root extract,melatonin, and PHARMACOAT® 615 hypromellose are prepared. The pH of thegranules is between 3.3-5. The microcrystalline cellulose (MCC),METHOCEL® K4M hypromellose and silicon dioxide are external to thegranules.

In the sustained release portion, intragranular hypromellose providesthe polymer matrix and also functions as a moisture and oxygen barrierto prevent oxidative degradation of the melatonin and valerian rootextract.

The expedited release portion is designed to release about 10% to about25% of the valerian root extract and melatonin within about one afteroral ingestion and the remaining melatonin and valerian over thefollowing 5 to 7 hours after oral ingestion.

The expedited release portion is prepared by combining the 98% salicinwhite willow bark extract, silicified MCC and magnesium stearate. Theexpedited release portion is designed to release substantially all ofthe white willow bark extract within about 30 minutes to 1 hour afteroral ingestion.

The expedited release and sustained release portions are compressedtogether into a bi-layer tablet or compressed individually to form twosmaller tablets. The tablets are finish coated with hypromellose orpolyvinylpyrrolidone for further stability protection and to help withswallowing.

Example 3 Melatonin, Valerian, and Salicin Composition

The product in this example is similar to that of Example 1, except thatthe expedited release portion includes granules including the valerianroot extract, PHARMACOAT® 615 hypromellose, and citric acid. Thecontents of this valerian product are summarized in Table 8.

TABLE 8 Contents of dosage form % w/w % w/w of Mass of dosage PortionIngredient (mg) portion form SR Valerian root extract 100 25.9 10intragranular SR melatonin 5 0.1 5 intragranular SR Hypromellose 14 361.4 intragranular (PHARMACOAT ® 615) SR Citric acid 65 16.8 6.6intragranular SR MCC 150 29.4 16 extragranular SR Hypromellose 50 9.85.4 extragranular (METHOCEL ® K4M) SR Silicon dioxide 2.5 0.49 0.27extragranular 386.5 ER Valerian root extract 100 17 10 intragranular ERHypromellose 14 23 1.4 intragranular (PHARMACOAT ® 615) ER Citric acid65 11 6.6 intragranular ER WWB extract 263 62.5 28 extragranular ERSilicified MCC 150 35.7 16 extragranular ER Mg stearate 7.5 1.8 0.8extragranular 599.5 TOTAL WEIGHT 986

Compared to the product in Example 2, this valerian product shifts halfof the valerian dose to the expedited release portion.

The expedited release portion is designed to release substantially allof the white willow bark extract and valerian root extract in it withinabout 30 minutes to 1 hour after oral ingestion.

This disclosure has described example embodiments, but not all possibleembodiments of the valerian product or associated methods. Where aparticular feature is disclosed in the context of a particularembodiment, that feature can also be used, to the extent possible, incombination with and/or in the context of other embodiments. Thevalerian product and related methods may be embodied in many differentforms and should not be construed as limited to only the embodimentsdescribed here.

That which is claimed is:
 1. A composition comprising an oralpharmaceutical dosage form comprising: a solid core including acombination of melatonin and a GABA receptor agonist ingredient locatedtogether within a first acidified polymeric matrix; an expedited releaseportion including a first portion of the GABA receptor agonistingredient in the solid core, the expedited release portion beingeffective to release substantially all of the GABA receptor agonistingredient therein within about 2 hours from placement in a 0.1 N HClsolution; and a sustained release portion including a second portion ofthe GABA receptor agonist ingredient in the solid core, the sustainedrelease portion being effective to release substantially all of the GABAreceptor agonist ingredient therein from at least 5 to about 8 hoursfrom placement in a phosphate buffer with a pH of 6.8.
 2. Thecomposition of claim 1, wherein the first acidified polymeric matrix hasa pH of about 1 to about 4.4.
 3. The composition of claim 1, wherein thesustained release portion includes a plurality of individual granulesthat have the remainder of the GABA receptor agonist ingredient in thepharmaceutical dosage form therein.
 4. The composition of claim 1,further comprising an analgesic ingredient in the expedited releaseportion.
 5. The composition of claim 1, further comprising an analgesicingredient in the expedited release portion; and wherein the sustainedrelease portion includes a plurality of individual granules that havethe remainder of the GABA receptor agonist ingredient in thepharmaceutical dosage form therein.
 6. The composition of claim 1,wherein the GABA receptor agonist ingredient includes valerian and theexpedited release portion further includes an analgesic ingredient. 7.The composition of claim 1, wherein the GABA receptor agonist ingredientincludes valerian and the expedited release portion further includes ananalgesic ingredient having salicin therein.
 8. The composition of claim1, wherein the pharmaceutical dosage form is at least one of acompressed tablet, capsule, and multiparticulate-containing oral dosageform.
 9. The composition of claim 1, wherein, in the expedited releaseportion, the 5% to 50% of the GABA receptor agonist ingredient in thepharmaceutical dosage form is located within a second acidifiedpolymeric matrix having a pH of about 1 to about 4.4.
 10. A compositioncomprising a pharmaceutical dosage form comprising: a solid coreincluding a combination of melatonin and an analgesic ingredient, themelatonin being located within a first acidified polymeric matrix with aGABA receptor agonist ingredient; an expedited release portion includinga first portion of the analgesic ingredient and the melatonin in thesolid core, the expedited release portion being effective to releasesubstantially all of the analgesic ingredient and melatonin thereinwithin about 2 hours from placement in a 0.1 N HCl solution; and asustained release portion including a second portion of the analgesicingredient and melatonin in the solid core, the sustained releaseportion being effective to release substantially all of the analgesicingredient and melatonin therein from at least 5 to about 8 hours fromplacement in a phosphate buffer with a pH of 6.8.
 11. The composition ofclaim 10, wherein the first acidified polymeric matrix has a pH of about1 to about 4.4.
 12. The composition of claim 10, wherein the sustainedrelease portion includes a plurality of individual granules that havethe remainder of the melatonin in the pharmaceutical dosage formtherein.
 13. The composition of claim 10, wherein the analgesicingredient includes a salicin source.
 14. The composition of claim 13,wherein the salicin source is a white willow bark extract that is atleast about 75% salicin.
 15. The composition of claim 10, wherein thepharmaceutical dosage form is at least one of a compressed tablet,capsule, and multiparticulate-containing oral dosage form.
 16. Thecomposition of claim 10, wherein, in the expedited release portion, the5% to 50% of the analgesic ingredient in the pharmaceutical dosage formis located within a second acidified polymeric matrix having a pH of 1to 4.4.
 17. A method of treatment comprising: administering to a patientin need thereof an effective amount of an oral pharmaceutical dosageform comprising: (a) a solid core including a combination of melatoninand a GABA receptor agonist ingredient located together within a firstacidified polymeric matrix; (b) an expedited release portion including afirst portion of the GABA receptor agonist ingredient in the solid core,the expedited release portion being effective to release substantiallyall of the GABA receptor agonist ingredient therein within about 2 hoursfrom placement in a 0.1 N HCl solution; and (c) a sustained releaseportion including a second portion of the GABA receptor agonistingredient in the solid core, the sustained release portion beingeffective to release substantially all of the GABA receptor agonistingredient therein from at least 5 to about 8 hours from placement in aphosphate buffer with a pH of 6.8.
 18. The method of claim 17, whereinthe first acidified polymeric matrix has a pH of about 1 to about 4.4.19. The method of claim 17, wherein the sustained release portionincludes a plurality of individual granules that have the second portionof the GABA receptor agonist ingredient in the pharmaceutical dosageform therein.
 20. The method of claim 17, wherein the oralpharmaceutical dosage form further comprises an analgesic ingredient inthe expedited release portion.
 21. The method of claim 17, wherein theoral pharmaceutical dosage form further comprises an analgesicingredient in the expedited release portion; and wherein the sustainedrelease portion includes a plurality of individual granules that havethe second portion of the GABA receptor agonist ingredient in thepharmaceutical dosage form therein.
 22. The method of claim 17, whereinthe GABA receptor agonist ingredient includes valerian and the expeditedrelease portion further includes an analgesic ingredient having salicintherein.
 23. The method of claim 17, wherein the pharmaceutical dosageform is at least one of a compressed tablet, capsule, andmultiparticulate-containing oral dosage form.